This invention relates to methods for treatment of bronchial asthma and other bronchospastic and allergic diseases. More particularly it relates to a method of treating these diseases employing certain substituted xanthine compounds.
Bronchial asthma is characterized by bronchospasm caused by contraction of the bronchial smooth muscle, increased secretion of mucus from the bronchi, and edema of the respiratory mucosa. While the etiology of asthma is not completely known, it is believed to involve an allergic reaction. Allergic reactions occur in sensitized individuals who are exposed to the antigen to which they are sensitized. The antigen provokes the release in the body of certain chemicals (allergic mediators) which in turn produce the allergic symptoms. Allergic reactions can also produce effects in organs other than the bronchi, particularly the skin, eyes and nasal mucosa and include such diseases as allergic rhinitis and urticaria.
Acute asthmatic bronchospasm has been treated with drugs which relax bronchial smooth muscle. Sympathominmetic drugs such as epinephrine, isoproterenol, and terbutaline and xanthine drugs such as theophylline and its salts (aminophylline, etc.) have been used for this purpose. Drugs such as cromolyn sodium which inhibit the release of allergic mediators, have been used prophylactically to treat bronchial asthma. Corticosteriod drugs have also been used to treat bronchial asthma and other allergy diseases.
Many of the drugs used hitherto have shortcomings which make them less than ideal for treatment of asthma and other bronchospastic and allergic diseases. For example, epinephrine and isoproterenol relieve the symptoms of asthma for only a relatively short period of time and are ineffective orally. Theophylline has limited efficacy and produces cardiac and gastrointestinal side effects. Cromolyn sodium is only effective by inhalation or injection and is ineffective by oral administration. The corticosteriod drugs have serious side effects which limit their chronic use.
Substituted xanthines have been known for some time as bronchodilators, and theophylline (1,3-dimethylxanthine) has long been used in the treatment of bronchial asthma.
Prior attempts have been made to improve theophylline by substituting the xanthine nucleus with different groups in several positions in the molecule. A number of 1,3-dialkylxanthines and 1,3,8-trialkylxanthines have been shown to be bronchodilators in animal models. However, none of the substituted xanthine compounds hitherto synthesized have displaced theophylline and its salts as clinically useful bronchodilator and antiallergy agents. There are several references in the prior art disclosing the synthesis of compounds which may be considered structurally similar to the compounds of the claimed invention. However, in each case where such similarity exists, either the degree and/or duration of activity of the claimed compounds is far superior to those of the prior art or a completely different utility is disclosed in connection with the prior art compounds. Stoll (Stoll, J. H., et.al., U.S. Pat. No. 2,729,643, issued Jan. 3, 1956), for example, discloses a method for forming substituted xanthines which are said to be effective as diuretics. At one stage in the Stoll process, an intermediate compound is formed which is illustrated by Stoll in the form of a generic structural formula, although the only specific example of a compound within the context of the general formula is 1,3-diethyl-7-carboethoxyxanthine. There is no specific disclosure of a 1,3,8-trialkyl-7-carboalkoxyxanthine, nor is there any disclosure in the patent of a 3-(2-methyl-1-butyl) substituted xanthine. Certain compounds disclosed by Vieth (Vieth, H., et.al., Biochem. Z. 163, 13-26 (1925).), Cacace, (Cacace, F., et.al., Ann. Chim. (Rome) 45, 983-993 (1955).), Giani, (Giani, M., et.al., Farmaco (Pavia), Ed. Sci. 12, 1016-1024 (1957).), may also be construed as being structurally similar to the compounds of this invention, but again none of these references suggests a bronchodilating or antiallergen use. They all acknowledge the diuretic use of theophylline derivatives although Cacace and Giani have no disclosure of a utility for the 7-carboalkoxy compounds discussed therein. Armitage, (Armitage, A. K., et.al., Brit. J. Pharmacol., 17, 196-207 (1961).), and Goodsell, (Goodsell, E. G. et.al., J. Med. Chem. 1971, 14 (12) 1202-1205.), both of whom deal with di- and tri-alkyl xanthines, allege uses relating to bronchodilation, but neither reference shows a 7-carboalkoxy substituent on a xanthine nucleus and substitution in the 3-position does not include a 2-methyl-1-butyl grouping. Thus, while a similar use is involved, the compounds of this invention are hot suggested by these prior art compounds. This is especially so in light of Beavo's disclosure (Beavo, J.A., et.al., Mol. Pharmacol. 1970, 6 (6) 597-603) that in studying the adenosine 3', 5' monophosphate phosphodiesterase (PDE) inhibiting activity of substituted xanthines, which is generally conceded to be correlated with bronchodilation activity, he noted that substitution in the 7-position either has no affect or decreases the potency of the compounds tested.
A class of substituted xanthine compounds has now been found which are very effective bronchodilator and antiallergy agents with rapid onset and prolonged duration of action. These compounds are effective, rapid-acting bronchodilators by all routes of administration and accordingly can be used to abort an acute bronchospastic attack. In addition, they are orally effective, long-acting antiallergy compounds, by suppressing the release of allergic mediators. Hence, these compounds may be used prophylactically to treat bronchial asthma, and other bronchospastic and allergic diseases.